CN106588811A - Method for asymmetrically synthesizing benzo sulfamide compound containing chiral quaternary carbon center - Google Patents
Method for asymmetrically synthesizing benzo sulfamide compound containing chiral quaternary carbon center Download PDFInfo
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- WDEMBUIMCANWOY-UHFFFAOYSA-N CCOC(C(CC(c1ccc(C)cc1)=O)(c1ccccc11)NS1(=O)=O)=O Chemical compound CCOC(C(CC(c1ccc(C)cc1)=O)(c1ccccc11)NS1(=O)=O)=O WDEMBUIMCANWOY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
Abstract
The invention relates to a method for asymmetrically synthesizing a benzo sulfamide compound containing a chiral quaternary carbon center. The method comprises the step that in an organic solvent, under the catalytic action of a chiral catalyst formed by complexing a bis-oxazoline chiral ligand L and metal M, an annular sulfimide and silyl enol ether serve as raw materials, and the benzo sulfamide compound containing the chiral quaternary carbon center is obtained through one step. The reaction yield is high (83%-99%), and the enantioselectivity is high (85%->99% ee). According to the method, the catalyst is simple, and the reaction condition is mild.
Description
Technical field
The invention belongs to technical field of organic synthesis, benzo of more particularly to a kind of asymmetric syntheses containing chiral quaternary carbon center
The method of interior sulfamide compound.
Background technology
In benzo sulfonamide backbones frequently as bioactive molecule important feature unit, such bioactive molecule by extensively should
For field (a.A.Mertens J.Med.Chem.1993,36,2526 such as agricultural chemicals, medicine and materials；b.M.Gao et
al.Eur.J.Med.Chem.2008,43,221；c.T.Nagase et al.,U.S.Patent6608098 B1,2003.).
For example part inhibitors of gamma-secretase, aldose reductase inhibitor and HIV-1 viral inhibitors are with sulfonamide in benzo as mother
Nuclear structure.On the other hand, using the chiral environment of compound itself, such compound can also regulate and control instead as chiral auxiliaries
The chemo-selective answered.
At present, from from the aspect of Atom economy and Green Chemistry, benzo of the most effective synthesis containing chiral quaternary carbon center
The method of interior sulfamide compound is that the alpha-position being catalyzed by chiral catalyst replaces N- sulfonyls cyclic imide and nucleopilic reagent
Addition reaction.Recently for over ten years, Chinese scholars use different chiral catalyst asymmetric syntheses containing different bones
Sulfamide compound in the benzo of frame：1) chiral palladium or rhodium catalyst catalysis alpha-position replace N- sulfonyls cyclic imide and aryl
Sulfamide compound (Hon in the benzo of the addition reaction synthesis containing chiral quaternary carbon center of boric acid or alkyl tetrafluoro boric acid sylvite
Wai Lam.Angew.Chem.Int.Ed.2012,51,8309–8313；Wanbin
Zhang.Angew.Chem.Int.Ed.2013,52,7540–7544；Ming-Hua Xu.J.Am.Chem.Soc.2013,135,
971-974).2) chiral amino thiocarbamide micromolecule catalyst or derived from chiral amino acid derived from the carbohydrate containing multifunctional dough
Sulfonyl hydrazines catalyst alpha-position replace the direct Mannich of N- sulfonyls cyclic imide and ketone to be synthesized containing chirality
Sulfamide compound (Zhiyong Wang, *, and Teck-Peng Loh* in the benzo of quaternary carbon center
.Org.Lett.2015,17,1050-1053；Jun-An Ma*.Org.Lett.2015,17,4608-4611).3) indoles or virtue
Base ethene in the presence of chiral A m indices catalyst, replaces N- sulfonyl cyclic imides with alpha-position respectively as nucleopilic reagent
The asymmetric Friedel-Crafts reaction of generation and ene reactions, to prepare quaternary carbon compound (Yi-Xia Jia*
.Adv.Synth.Catal.2015,357,709–713；ACS Catal.2015,5,6524-6528.).4) chirality NHC catalysis
Agent, phosphine catalyst or β-ICD are catalyzed respectively unsaturated aldehyde, connection alkene and MBH addition products derived from isatin and alpha-position replaces N- sulphonyl
The cycloaddition reaction of base cyclic imide obtains containing multiple adjacent chiral centres and cyclic sulfonamides class compound (Yonggui
Robin Chi*.Chem.Eur.J.2015,21,9984–9987；Li Liu*.Org.Lett.,2015,17,1688–1691；
Hiroaki Sasai*.Asian J.Org.Chem.2014,3,412–415)。
In the Mannich reactions that the N- sulfonyls cyclic imide of organocatalysis is participated in, aryl is particularly prepared
The optical activity of the chiral quaternary carbon compound that ketone replaces is poor relative to the product that alkyl ketone replaces.So explore new synthesis containing
The method for having sulfamide compound in the benzo of chiral quaternary carbon center still has great importance.
The content of the invention
To solve above-mentioned technical problem, the invention provides sulphur in a kind of benzo of asymmetric syntheses containing chiral quaternary carbon center
The method of amides compound.The technical solution used in the present invention is：
The method of sulfamide compound in a kind of benzo of asymmetric syntheses containing chiral quaternary carbon center, it is, organic
The salt of ， bisoxazolines chiral ligand L and metal M is complexed the chiral catalyst asymmetry catalysis ring-type sulfimide to be formed in solvent
Mukaiyama-Mannich reactions are carried out with silyl enol ether, sulfamide compound in synthesis benzo, reaction equation is as follows：
In formula：R1Selected from methyl, trifluoromethyl, the tert-butyl group, methoxyl group, trifluoromethoxy, fluorine, chlorine, bromine, hydrogen；Ar is virtue
Perfume base；Metal M is selected from nickel, zinc, cobalt.
In one embodiment, the substituent of the bisoxazoline chiral ligand L is selected from phenyl, benzyl, isopropyl, uncle
Butyl.Preferably, the bisoxazoline chiral ligand L is the Evans Xing bisoxazoline chiral ligands that 4 phenyl replace.
In one embodiment, the salt of the metal M is selected from NiCl2、Ni(ClO4)2.6H2O、Ni(OAc)2、Ni
(OTf)2、Ni(acac)2、Co(ClO4)2·6H2O、Zn(OTf)2、Zn(ClO4)2·6H2O。
In one embodiment, the silyl enol ether is silyl enol ether derived from aromatic ketone.
In one embodiment, the silyl enol ether, Ar be phenyl, the phenyl with substituent, naphthyl, furyl or
Thienyl；The phenyl with substituent, substituent selected from methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, the tert-butyl group,
Fluorine, chlorine, bromine, nitro.
In one embodiment, the organic solvent is selected from methyl alcohol, tetrahydrofuran, toluene, dichloromethane, three chloromethanes
Alkane, ether, 1,2- dichloroethanes, ethyl acetate；Preferably chloroform.
In one embodiment, the temperature range of the Mukaiyama-Mannich reactions of the asymmetry catalysis is -20
～25 DEG C；Preferably -20～0 DEG C.
In one embodiment, the Mukaiyama-Mannich reactions bisoxazolines used of the asymmetry catalysis
The molar equivalent ratio of the salt of chiral ligand L and metal M is 1.1:(0.1～1).
In one embodiment, the Mukaiyama-Mannich reactions of asymmetry catalysis ring-type sulphur used is sub-
Amine is 1 with the molar equivalent ratio of silyl enol ether:1～1:5.
In one embodiment, the salt of the Mukaiyama-Mannich reactions of asymmetry catalysis metal M used
It is 1mol%～20mol% with the molar equivalent ratio of ring-type sulfimide；Preferably 1mol%～10mol%.
Beneficial effects of the present invention are：
The inventive method reaction yield is high, and optical purity is high, and catalyst is simple, and reaction condition is gentle.The inventive method can
As the synthetics of sulfamide compound in the benzo with important biomolecule activity and using value.
Specific embodiment
With reference to specific embodiment, the present invention will be further described.It is emphasized that the description below is only
Exemplary, rather than in order to limit the scope of the present invention and its application.
By in organic solvent, chiral catalyst that the salt of bisoxazoline chiral ligand L and metal M is complexed is urged
Under change effect, with ring-type sulfimide and silyl enol ether as raw material, a step obtains sulphonyl in the benzo containing chiral quaternary carbon center
Aminated compounds, reaction yield height (83%～99%), enantioselectivity height (85%～＞ 99%ee).
Evans Xing bisoxazoline chiral ligand (S, the S- for adding 4 phenyl to replace in dry 25mL round-bottomed flasks
Ph-BOX, shown in formula I) (3.7mg, 0.011mmol), Ni (ClO4)2·6H2O (3.6mg, 0.010mmol), adds and is dried three
Chloromethanes 1.5mL, under nitrogen protection 2h is stirred at room temperature, and adds ring-type sulphur imines (0.1mmol) of different replacements, is stirred at room temperature
Be cooled with an ice bath after 30 minutes, add silyl enol ether (0.2mmol), stirring reaction 10h is continued at 0 DEG C (referring to Formula II).Thin layer
Chromatogram monitoring reaction process, question response is finished, directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing,
Obtain product.
Table 1 is to be synthesized containing chiral quaternary carbon center using said method asymmetry catalysis Mukaiyama-Mannich
Benzo in sulfamide compound example.
Asymmetry catalysis Mukaiyama-the Mannich of table 1 are synthesized sulfonamide in the benzo containing chiral quaternary carbon center
Class compound data table
The present invention is further illustrated below by specific embodiment：
1) synthesis of benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide：
4.3g (20mmol) N- tert-butyl benzene sulfonamide, dry tetrahydrofuran 60mL are added in 150mL round-bottomed flasks.
Under nitrogen protection, n-BuLi (50mmol) is slowly added dropwise at -78 DEG C, 0 DEG C is to slowly warm up to, at 0 DEG C 2h is stirred；
Reaction system is cooled to again -78 DEG C, is added dropwise over ethyl oxalate (60mmol), stirs 20min, is to slowly warm up to be stirred at room temperature
1h.The quenching reaction of the 30mL 5wt%HCl aqueous solution, ethyl acetate is added to extract three times (50mL ethyl acetate × 3 time), saturation chlorine
Change sodium solution washing organic phase, anhydrous sodium sulfate drying 4h, the hemiacetal intermediate product that removal of solvent under reduced pressure is obtained is not purified
It is directly used in next step reaction；Under nitrogen protection, hemiacetal intermediate product is dissolved in 25mL anhydrous formic acids, in 35 DEG C of stirrings
48h.After question response is complete, anhydrous formic acid is removed under reduced pressure, is dissolved with dichloromethane, washed with 50mL saturated sodium bicarbonate aqueous solutions
To remove a small amount of anhydrous formic acid, solvent is sloughed in anhydrous sodium sulfate drying 4h, decompression, and it is different that column chromatography obtains after purification benzo [d]
Thiazole -3- carboxylic acid, ethyl esters -1,1- dioxide 3.3g (69%yield).
Different R1The synthesis of substituted ring-type sulfimine compound can be prepared using same procedure.
2) synthesis of 1- trimethylsiloxy groups -1- phenylethylenes：
In 25mL round-bottomed flasks, 0.6g (5mmol) acetophenone is added, be slowly added dropwise the four of 6mL 1mol/L LiHMDS
30min is stirred under hydrogen tetrahydrofuran solution, room temperature, 0.7g TMSCl (6.5mmol) are added, continues to stir 30min, decompression is sloughed molten
Agent, adds 15mL petroleum ethers, is filtered with diatomite, and filtrate Jing column chromatographies purifying obtains 1- trimethylsiloxy group -1- phenylethylenes
0.8g (83%yield).
Ar is that the synthesis of the silyl enol ether of the phenyl with different substituents can be prepared using same procedure.
Embodiment 1
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), add dry methylene chloride 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then add
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 10h at 0 DEG C.Question response is finished,
Directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, white solid 34mg (95%yield) is obtained.
1H NMR(300MHz,CDCl3)δ7.95–7.87(m,2H),7.85–7.78(m,1H),7.75–7.53(m,4H),
7.50-7.41 (m, 2H), 6.09 (s, 1H), 4.31 (qq, J=10.8,7.2Hz, 2H), 4.08 (d, J=17.8Hz, 1H),
3.72 (d, J=17.8Hz, 1H), 1.29 (t, J=7.1Hz, 3H) .13C NMR (75MHz, CDCl3) δ 195.65,169.27,
136.60,135.28,133.67,133.33,130.49,128.47,127.86,123.92,121.54,65.16,63.17,
48.81,13.61.(c,1.20,CH2Cl2)；HPLC analysis:Daicel Chiralcel OD-H,
N-hexane/i-PrOH=80:20,1.0mL/min,220nm；tR(major)=17.85min, tR(minor)=
24.75min；99%ee.
Embodiment 2
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Zn are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), add dry methylene chloride 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then add
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 10h, reactant mixture at 0 DEG C
Directly by silica gel column chromatography separating-purifying after decompression desolventizing, white solid 30mg (83%yield) is obtained.
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.57min, tR(minor)=24.66min；95%ee.
Embodiment 3
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Co are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), add dry methylene chloride 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then add
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 10h at 0 DEG C.Question response is finished,
Directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, white solid 33mg (92%yield) is obtained.
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.57min, tR(minor)=24.66min；97%ee.
Embodiment 4
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 10h at 0 DEG C.Question response is finished,
Directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, white solid 35.5mg (99% is obtained
yield)。
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.89min, tR(minor)=24.79min；99%ee.
Embodiment 5
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), add and are dried 1,2- dichloroethanes 1.5mL, and 2h is stirred at room temperature under nitrogen protection,
Benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1 is added, 1- dioxide (24mg, 0.1mmol) is used after being stirred at room temperature 30 minutes
Ice bath is cooled down, and adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 10h at 0 DEG C.Question response
Finish, directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtain white solid 34.8mg (97%
yield)。
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.79min, tR(minor)=24.69min；97%ee.
Embodiment 6
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), add and are dried 1,2- dichloroethanes 1.5mL, and 2h is stirred at room temperature under nitrogen protection,
Benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1 is added, 1- dioxide (24mg, 0.1mmol) is used after being stirred at room temperature 30 minutes
Ice bath is cooled down, and adds 1- trimethylsiloxy groups -1- phenylethylenes (19mg, 0.1mmol), continues to stir 10h at 0 DEG C.Question response
Finish, directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtain white solid 33.7mg (94%
yield)。
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.64min, tR(minor)=24.57min；99%ee.
Embodiment 7
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), add and are dried 1,2- dichloroethanes 1.5mL, and 2h is stirred at room temperature under nitrogen protection,
Benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1 is added, 1- dioxide (24mg, 0.1mmol) is used after being stirred at room temperature 30 minutes
Ice bath is cooled down, and adds 1- trimethylsiloxy groups -1- phenylethylenes (96mg, 0.5mmol), continues to stir 10h at 0 DEG C.Question response
Finish, directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtain white solid 35.2mg (98%
yield)。
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.76min, tR(minor)=24.69min；91%ee.
Embodiment 8
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol), after being stirred at room temperature 30 minutes, be put into -
20 DEG C of ice bath coolings, add 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continue to stir 20h at -20 DEG C.
Question response is finished, and directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtains white solid
35.6mg (99%yield).
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.75min, tR(minor)=24.85min；99%ee.
Embodiment 9
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
Add in dry 25mL round-bottomed flasks (S, S-Ph-BOX) bisoxazolines ligand 1 .9mg (0.0055mmol),
Ni(ClO4)2·6H2O 1.8mg (0.005mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then
Benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) is added to use ice after being stirred at room temperature 30 minutes
Bath cooling, adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 10h at 0 DEG C.Question response is complete
Finish, directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtain white solid 35.5mg (99%
yield)。
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.75min, tR(minor)=24.85min；99%ee.
Embodiment 10
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
Add in dry 25mL round-bottomed flasks (S, S-Ph-BOX) bisoxazolines part 0.37mg (0.0011mmol),
Ni(ClO4)2·6H2O 0.36mg (0.001mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection,
Benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1 is added, 1- dioxide (24mg, 0.1mmol) is used after being stirred at room temperature 30 minutes
Ice bath is cooled down, and adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 40h at 0 DEG C.Question response
Finish, directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtain white solid 33mg (92%
yield)。
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.75min, tR(minor)=24.85min；96%ee.
Embodiment 11
3- (2- oxo -2- (4- aminomethyl phenyl ethyls)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl esters -1,1- two
The synthesis of oxide：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds trimethyl ((1-4- methyl phenyl vinyls) epoxide) silane (41mg, 0.2mmol), continues to stir 10h at 0 DEG C.
Question response is finished, and directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtains white solid 37mg
(99%yield).
1H NMR(300MHz,CDCl3)δ7.86–7.77(m,3H),7.73–7.59(m,3H),7.29–7.23(m,2H),
6.09 (s, 1H), 4.39-4.22 (m, 2H), 4.07 (d, J=17.7Hz, 1H), 3.70 (d, J=17.7Hz, 1H), 2.41 (s,
3H), 1.30 (t, J=7.1Hz, 3H).13C NMR(75MHz,CDCl3)δ195.22,169.33,144.67,136.65,
135.26,133.29,132.86,130.43,129.13,127.98,123.95,121.50,65.21,63.10,48.70,
21.37,13.60.(c,1.26,CH2Cl2)；HPLC analysis:Daicel Chiralcel OD-H,
N-hexane/i-PrOH=80:20,1.0mL/min,220nm；tR(major)=16.90min, tR(minor)=
19.91min；99%ee.
Embodiment 12
3- (2- oxo -2- (4- bromophenyl ethyls)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxies
The synthesis of compound：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds trimethyl ((1-4- bromophenyl vinyl) epoxide) silane (54mg, 0.2mmol), continues to stir 10h at 0 DEG C.Treat
Reaction is finished, and directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtains white solid 39mg
(89%yield).
1H NMR(300MHz,CDCl3) δ 7.88-7.57 (m, 8H), 6.15 (s, 1H), 4.34 (qq, J=10.8,7.1Hz,
2H), 4.08 (d, J=17.8Hz, 1H), 3.70 (d, J=17.8Hz, 1H), 1.32 (t, J=7.1Hz, 3H).13C NMR
(75MHz,CDCl3)δ194.74,169.15,136.44,135.18,133.98,133.44,131.80,130.58,129.36,
128.99,123.95,121.51,77.20,76.78,76.36,65.06,63.27,48.64,13.63.
(c,1.0,CH2Cl2)；HPLC analysis(Chiralcel OD-H,n-hexane:i-PrOH 80:20,1.0mL/min,tr
(minor)=21.772min, tr(major)=31.212min, 98.5%ee).
Embodiment 13
3- (2- oxo -2- (3- methoxyphenyl ethyls)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1-
The synthesis of dioxide：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds trimethyl ((1-3- methoxyphenyl vinyl) epoxide) silane (45mg, 0.2mmol), continues to stir at 0 DEG C
10h.Question response is finished, and directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtains white solid
38.2mg (98%yield).
1H NMR(300MHz,CDCl3)δ7.86–7.80(m,1H),7.75–7.58(m,3H),7.51–7.42(m,2H),
7.40-7.32 (m, 1H), 7.17-7.11 (m, 1H), 6.08 (s, 1H), 4.32 (qq, J=10.7,7.1Hz, 2H), 4.07 (d, J
=17.8Hz, 1H), 3.84 (s, 3H), 3.71 (d, J=17.8Hz, 1H), 1.31 (t, J=7.1Hz, 3H).13C NMR
(75MHz,CDCl3)δ195.50,169.24,159.63,136.62,135.31,133.31,130.48,129.44,123.92,
121.53,120.52,120.29,111.94,65.18,63.17,55.16,48.89,13.62.(c,
1.09,CH2Cl2)；Daicel HPLC analysis:Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/
min,220nm；tR(major)=22.95min, tR(minor)=69.05min；98%ee.
Embodiment 14
3- (2- oxo -2- (2- fluorophenylethyls)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxies
The synthesis of compound：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds trimethyl ((1-2- fluorophenyl vinyl) epoxide) silane (42mg, 0.2mmol), continues to stir 10h at 0 DEG C.Treat
Reaction is finished, and directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtains white solid 37mg
(98%yield).
1H NMR(300MHz,CDCl3)δ7.99–7.89(m,1H),7.86–7.80(m,1H),7.76–7.50(m,4H),
7.31-7.23 (m, 1H), 7.19-7.09 (m, 1H), 6.06 (s, 1H), 4.32 (qq, J=10.7,7.1Hz, 2H), 4.14 (dd,
J=18.6,3.7Hz, 1H), 3.67 (dd, J=18.6,3.6Hz, 1H), 1.31 (t, J=7.1Hz, 3H).13C NMR(75MHz,
CDCl3) δ 193.54 (d, J=3.9Hz), 169.29,162.06 (d, J=255.7Hz), 136.41,135.45 (d, J=
9.3Hz), 135.18,133.34,130.46,130.37 (d, J=2.1Hz), 124.41 (d, J=3.3Hz), 123.97,
123.64 (d, J=12.4Hz), 121.52,116.46 (d, J=23.6Hz), 65.16 (d, J=3.2Hz), 63.14,53.41
(d, J=9.0Hz), 13.60.(c,1.11,CH2Cl2)；HPLC analysis:Daicel
Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,220nm；tR(major)=12.69min, tR
(minor)=15.30min；99%ee.
Embodiment 15
3- (2- oxo -2- (thienyl base ethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxies
The synthesis of compound：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds trimethyl ((thienyl vinyl) epoxide) silane (40mg, 0.2mmol), continues to stir 10h at 0 DEG C.Question response
Finish, directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtain white solid 35.4mg (97%
yield)。
1H NMR(300MHz,CDCl3)δ7.83–7.78(m,1H),7.76–7.57(m,5H),7.15–7.10(m,1H),
6.09 (s, 1H), 4.42-4.22 (m, 2H), 4.04 (d, J=17.4Hz, 1H), 3.65 (d, J=17.4Hz, 1H), 1.31 (t, J
=7.1Hz, 3H).13C NMR(75MHz,CDCl3)δ188.27,169.04,142.17,136.47,135.21,134.57,
133.41,132.76,130.54,128.10,124.01,121.45,65.16,63.27,48.86,13.61.(c,1.14,CH2Cl2)；HPLC analysis:Daicel Chiralcel OD-H column,n-
Hexane/i-PrOH=80:20,1.0mL/min,220nm；T (minor)=20.85min, t (major)=23.03min；
97%ee.
Embodiment 16
3- (2- oxo -2- (phenylethyl)) -5- methoxyl group -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,
The synthesis of 1- dioxide：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter 5- methoxyl groups-benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (27mg, 0.1mmol) is stirred at room temperature 30 minutes
After be cooled with an ice bath, add 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), at 0 DEG C continue stir 10h.Treat
Reaction is finished, and directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtains white solid 38.5mg
(99%yield).
1H NMR(300MHz,CDCl3)δ7.95–7.86(m,2H),7.74–7.66(m,1H),7.63–7.54(m,1H),
7.50-7.40 (m, 2H), 7.15-7.08 (m, 2H), 6.09 (s, 1H), 4.44-4.20 (m, 2H), 4.08 (d, J=17.8Hz,
1H), 3.91 (s, 3H), 3.72 (d, J=17.8Hz, 1H), 1.30 (t, J=7.1Hz, 3H).13C NMR(75MHz,CDCl3)δ
195.65,169.27,163.62,139.18,135.29,133.63,128.44,127.84,127.19,122.88,116.94,
108.30,64.85,63.11,55.73,48.94,13.65.(c,0.67,CH2Cl2)；HPLC
analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,220nm；tR
(major)=14.83min, tR(minor)=22.17min；＞ 99%ee.
Embodiment 17
Chloro- 2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl esters -1,1- two of 3- (2- oxo -2- (phenylethyl)) -7-
The synthesis of oxide：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter 7- chloro- benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (27.5mg, 0.1mmol), after being stirred at room temperature 30 minutes
It is cooled with an ice bath, adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 10h at 0 DEG C.Treat anti-
Should finish, directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtain white solid 38.5mg
(98%yield).
1H NMR(300MHz,CDCl3)δ7.95–7.86(m,2H),7.68–7.52(m,4H),7.49–7.42(m,2H),
6.20 (s, 1H), 4.33 (qq, J=10.7,7.1Hz, 2H), 4.05 (d, J=17.7Hz, 1H), 3.73 (d, J=17.7Hz,
1H), 1.31 (t, J=7.1Hz, 3H).13C NMR(75MHz,CDCl3)δ195.28,168.83,139.36,135.17,
134.48,133.75,133.36,131.25,129.19,128.50,127.85,122.25,64.20,63.43,48.61,
13.61.(c,1.23,CH2Cl2)；HPLC analysis:aicel Chiralcel AD-H,n-
Hexane/i-PrOH=70:30,0.9mL/min,220nm；tR(minor)=19.91min, tR(major)=26.94min；
97%ee.
Embodiment 18
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Zn are added in dry 25mL round-bottomed flasks
(OTf)23.6mg (0.010mmol), adds dry methylene chloride 1.5mL, and 2h is stirred at room temperature under nitrogen protection, adds benzo
[d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) is cooled with an ice bath after being stirred at room temperature 30 minutes, plus
Enter 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continue to stir 10h at 0 DEG C.Question response is finished, and reaction is mixed
Directly by silica gel column chromatography separating-purifying after compound decompression desolventizing, white solid 30mg (83%yield) is obtained.
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.57min, tR(minor)=24.66min；95%ee.
Embodiment 19
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 3.6mg (0.010mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) stirs 30min, adds 1- at 25 DEG C
Trimethylsiloxy group -1- phenylethylenes (38mg, 0.2mmol), continues to stir 5h at 25 DEG C.Question response is finished, reactant mixture
Directly by silica gel column chromatography separating-purifying after decompression desolventizing, white solid 35mg (99%yield) is obtained.
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.55min, tR(minor)=24.65min；85%ee.
Embodiment 20
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 1.8mg (0.005mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 10h at 0 DEG C.Question response is finished,
Directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, white solid 35mg (99%yield) is obtained.
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.75min, tR(minor)=24.85min；99%ee.
Embodiment 21
3- (2- oxo -2- (phenylethyl)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide
Synthesis：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 0.36mg (0.001mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then
Benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) is added to use ice after being stirred at room temperature 30 minutes
Bath cooling, adds 1- trimethylsiloxy groups -1- phenylethylenes (38mg, 0.2mmol), continues to stir 40h at 0 DEG C.Question response is complete
Finish, directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtain white solid 33mg (90%
yield)。
HPLC analysis:Daicel Chiralcel OD-H, n-hexane/i-PrOH=80:20,1.0mL/min,
220nm；tR(major)=17.75min, tR(minor)=24.85min；96%ee.
Embodiment 22
3- (2- oxo -2- (4- aminomethyl phenyl ethyls)) -2,3- dihydrobenzos [d] isothiazole -3- carboxylic acid, ethyl esters -1,1- two
The synthesis of oxide：
(S, S-Ph-BOX) bisoxazolines part 3.7mg (0.011mmol), Ni are added in dry 25mL round-bottomed flasks
(ClO4)2·6H2O 1.8mg (0.005mmol), addition is dried chloroform 1.5mL, and 2h is stirred at room temperature under nitrogen protection, then adds
Enter benzo [d] isothiazole -3- carboxylic acid, ethyl ester -1,1- dioxide (24mg, 0.1mmol) uses ice bath after being stirred at room temperature 30 minutes
Cooling, adds trimethyl ((1-4- methyl phenyl vinyls) epoxide) silane (41mg, 0.2mmol), continues to stir at 0 DEG C
40h.Question response is finished, and directly by silica gel column chromatography separating-purifying after reactant mixture decompression desolventizing, obtains white solid
37mg (99%yield).
1H NMR(300MHz,CDCl3)δ7.86–7.77(m,3H),7.73–7.59(m,3H),7.29–7.23(m,2H),
6.09 (s, 1H), 4.39-4.22 (m, 2H), 4.07 (d, J=17.7Hz, 1H), 3.70 (d, J=17.7Hz, 1H), 2.41 (s,
3H), 1.30 (t, J=7.1Hz, 3H).13C NMR(75MHz,CDCl3)δ195.22,169.33,144.67,136.65,
135.26,133.29,132.86,130.43,129.13,127.98,123.95,121.50,65.21,63.10,48.70,
21.37,13.60.(c,1.26,CH2Cl2)；HPLC analysis:Daicel Chiralcel OD-H,
N-hexane/i-PrOH=80:20,1.0mL/min,220nm；tR(minor)=19.62min, tR(major)=
20.80min；97%ee.
Claims (10)
1. a kind of method that asymmetric syntheses contains sulfamide compound in the benzo of chiral quaternary carbon center, it is characterised in that
The salt of ， bisoxazolines chiral ligand L and metal M is complexed the chiral catalyst asymmetry catalysis ring-type sulphonyl to be formed in organic solvent
Imines carries out Mukaiyama-Mannich reactions with silyl enol ether, and sulfamide compound in synthesis benzo, reaction equation is as follows：
In formula：R1Selected from methyl, trifluoromethyl, the tert-butyl group, methoxyl group, trifluoromethoxy, fluorine, chlorine, bromine, hydrogen；Ar is aromatic radical；
Metal M is selected from nickel, zinc, cobalt.
2. method according to claim 1, it is characterised in that the substituent of the bisoxazoline chiral ligand L is selected from benzene
Base, benzyl, isopropyl, the tert-butyl group.
3. method according to claim 1, it is characterised in that the salt of the metal M is selected from NiCl2、Ni(ClO4)2.6H2O、
Ni(OAc)2、Ni(OTf)2、Ni(acac)2、Co(ClO4)2·6H2O、Zn(OTf)2、Zn(ClO4)2·6H2O。
4. method according to claim 1, it is characterised in that the silyl enol ether is silyl enol ether derived from aromatic ketone.
5. the method according to claim 1 or 4, it is characterised in that the silyl enol ether, Ar is phenyl, with substituent
Phenyl, naphthyl, furyl or thienyl；
The phenyl with substituent, substituent selected from methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, the tert-butyl group, fluorine,
Chlorine, bromine, nitro.
6. method according to claim 1, it is characterised in that the organic solvent selected from methyl alcohol, tetrahydrofuran, toluene,
Dichloromethane, chloroform, ether, 1,2- dichloroethanes, ethyl acetate.
7. method according to claim 1, it is characterised in that the Mukai yama-Mannich of the asymmetry catalysis are anti-
The temperature range answered is -20～25 DEG C.
8. method according to claim 1, it is characterised in that the Mukai yama-Mannich of the asymmetry catalysis are anti-
The molar equivalent ratio for answering the salt of bisoxazoline chiral ligand L and metal M used is 1.1:(0.1～1).
9. method according to claim 1, it is characterised in that the Mukai yama-Mannich of the asymmetry catalysis are anti-
Ring-type sulphur imines and the molar equivalent ratio of silyl enol ether that should be used be 1:1～1:5.
10. method according to claim 1, it is characterised in that the Mukaiyama-Mannich of the asymmetry catalysis are anti-
The salt of metal M that should be used is 1mol%～20mol% with the molar equivalent ratio of ring-type sulfimide.
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Non-Patent Citations (4)
| Title |
|---|
| JIN-SHENG YU 等: "A highly efficient Mukaiyama–Mannich reaction of N-Boc isatin ketimines and other active cyclic ketimines using difluoroenol silyl ethers catalyzed by Ph3PAuOTf", 《ORGANIC BIOMOLECULAR CHEMISTRY》 * |
| JIN-SHENG YU 等: "Organocatalytic enantioselective Mukaiyama–Mannich reaction of fluorinated enol silyl ethers and cyclic N-sulfonyl ketimines", 《ORG. CHEM. FRONT.》 * |
| SHENG ZHANG 等: "Bifunctional Amino Sulfonohydrazide Catalyzed Direct Asymmetric Mannich Reaction of Cyclic Ketimines with Ketones: Highly Diastereo- and Enantioselective Construction of Quaternary Carbon Stereocenters", 《ORG. LETT.》 * |
| 刘磊: "手性芳甲叉双噁唑啉和双噻唑啉配体在不对称催化反应中的应用", 《中国博士学位论文全文数据库》 * |
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